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Identification of immucillin analogue natural compounds to inhibit Helicobacter pylori MTAN through high throughput
Divya S Raj1, Chidhambara Priya Dharshini Kottaisamy1, Waheetha Hopper2
1Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627 012 India.
Abstract:
One in every two humans is having Helicobacter pylori (H. pylori) in stomach causing gastric ulcer. Emergence of several drugs in eliminating H. pylori has paved way for emergence of multidrug resistance in them. This resistance is thriving and thereby necessitating the need of a potent drug. Identifying a potential target for medication is crucial. Bacterial 5'-methylthioadenosine/S-enosyl homocysteine nucleosidase (MTAN) is a multifunctional enzyme that controls seven essential metabolic pathways. It functions as a catalyst in the hydrolysis of the N-ribosidic bond of adenosine-based metabolites: S-adenosylhomocysteine (SAH), 5'-methylthioadenosine (MTA), 5'-deoxyadenosine (5'-DOA), and 6-amino-6-deoxyfutalosine. H. pylori unlike other bacteria and humans utilises an alternative pathway for menaquinone synthesis. It utilises Futosiline pathway for menaquinone synthesis which are obligatory component in electron transport pathway. Therefore, the enzymes functioning in this pathway represent them-self as a point of attack for new medications. We targeted MTAN protein of H. pylori to find out a potent natural hit to inhibit its growth. A comparative analysis was made with potent H. pylori MTAN (HpMTAN) known inhibitor, 5'-butylthio-DADMe-Immucillin-A (BuT-DADMe-ImmA) and ZINC natural subset database. Optimized ligands from the ZINC natural database were virtually screened using ligand based pharmacophore hypothesis to obtain the most efficient and potent inhibitors for HpMTAN. The screened leads were evaluated for their therapeutic likeness. Furthermore, the ligands that passed the test were subjected for MM-GBSA with MTAN to reveal the essential features that contributes selectivity. The results showed that Van der Waals contributions play a central role in determining the selectivity of MTAN. Molecular dynamics (MD) studies were carried out for 100 ns to assess the stability of ligands in the active site. MD analysis showed that binding of ZINC00490333 with MTAN is stable compared to reference inhibitor molecule BuT-DADMe-ImmA. Among the natural inhibitors screened after various docking procedures ZINC00490333 has highest binding score for HpMTAN (- 13.987). The ZINC inhibitor was successful in reproducing the BuT-DADMe-ImmA interactions with HpMTAN. Hence we suggest that ZINC00490333 compound may represent as a good lead in designing novel potent inhibitors of HpMTAN. This in silico approach indicates the potential of this molecule for advancing a further step in gastric ulcer treatment.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s40203-021-00081-2.
Insights
Multidrug-resistant Helicobacter pylori (H. pylori) causes gastric ulcers. Researchers identified ZINC00490333 as a potent natural inhibitor of H. pylori MTAN, showing stable binding and potential for new gastric ulcer treatments.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Helicobacter pylori (H. pylori) infection is a major cause of gastric ulcers.
- Emerging multidrug resistance in H. pylori necessitates novel therapeutic strategies.
- Bacterial 5'-methylthioadenosine/S-enosyl homocysteine nucleosidase (MTAN) is a key enzyme in essential metabolic pathways.
Purpose of the Study:
- To identify potent natural inhibitors of H. pylori MTAN (HpMTAN) for potential gastric ulcer treatment.
- To evaluate the therapeutic likeness and binding stability of natural compounds against HpMTAN.
- To explore novel drug targets in the H. pylori menaquinone synthesis pathway.
Main Methods:
- Virtual screening of a natural product database against HpMTAN using pharmacophore hypothesis.
- Molecular docking and MM-GBSA calculations to assess binding affinity and selectivity.
- Molecular dynamics (MD) simulations to evaluate ligand-target complex stability.
Main Results:
- ZINC00490333 demonstrated the highest binding affinity and stability against HpMTAN compared to a known inhibitor.
- Van der Waals interactions were identified as crucial for selective MTAN inhibition.
- MD studies confirmed the stable binding of ZINC00490333 within the HpMTAN active site.
Conclusions:
- ZINC00490333 is a promising natural lead compound for developing new H. pylori inhibitors.
- This in silico approach highlights the potential of targeting HpMTAN for gastric ulcer therapy.
- Further experimental validation is warranted to advance ZINC00490333 for clinical application.
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